Development of a New BCMAxCD3 Duobody® Antibody for Multiple Myeloma

Pillarisetti, Kodandaram; Baldwin, Eric T.; Babich, Alexander; Majewski, Nate; Barone, Linda; Li, Yingzhe; Zhang, Xiaochun; Chin, Diana; Luistro, Leopoldo; Mendonca, Mark; Nanjunda, Rupesh; Rudnick, Stephen I.; Bellew, Kevin M.; Elsayed, Yusri; Attar, Ricardo M.; Gaudet, François

doi:10.1182/blood.v128.22.2116.2116

Cited by 8 publications

(7 citation statements)

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“…Ab-957 is bispecific IgG-like Ab generated by Genmab DuoBody ® technology to target CD3 on T cells and BCMA on MM cells ( 102 ). Preclinical studies also show that Ab-957 potently induces specific cytotoxicity of BCMA + MM cells in vitro and in vivo , with a concomitant activation of T cells at very low concentration.…”

Section: Anti-bcma Cd3 Bi- or Trispecific Moleculesmentioning

confidence: 99%

Targeting B Cell Maturation Antigen (BCMA) in Multiple Myeloma: Potential Uses of BCMA-Based Immunotherapy

2018

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The approval of the first two monoclonal antibodies targeting CD38 (daratumumab) and SLAMF7 (elotuzumab) in late 2015 for treating relapsed and refractory multiple myeloma (RRMM) was a critical advance for immunotherapies for multiple myeloma (MM). Importantly, the outcome of patients continues to improve with the incorporation of this new class of agents with current MM therapies. However, both antigens are also expressed on other normal tissues including hematopoietic lineages and immune effector cells, which may limit their long-term clinical use. B cell maturation antigen (BCMA), a transmembrane glycoprotein in the tumor necrosis factor receptor superfamily 17 (TNFRSF17), is expressed at significantly higher levels in all patient MM cells but not on other normal tissues except normal plasma cells. Importantly, it is an antigen targeted by chimeric antigen receptor (CAR) T-cells, which have already shown significant clinical activities in patients with RRMM who have undergone at least three prior treatments, including a proteasome inhibitor and an immunomodulatory agent. Moreover, the first anti-BCMA antibody–drug conjugate also has achieved significant clinical responses in patients who failed at least three prior lines of therapy, including an anti-CD38 antibody, a proteasome inhibitor, and an immunomodulatory agent. Both BCMA targeting immunotherapies were granted breakthrough status for patients with RRMM by FDA in Nov 2017. Other promising BCMA-based immunotherapeutic macromolecules including bispecific T-cell engagers, bispecific molecules, bispecific or trispecific antibodies, as well as improved forms of next generation CAR T cells, also demonstrate high anti-MM activity in preclinical and even early clinical studies. Here, we focus on the biology of this promising MM target antigen and then highlight preclinical and clinical data of current BCMA-targeted immunotherapies with various mechanisms of action. These crucial studies will enhance selective anti-MM response, transform the treatment paradigm, and extend disease-free survival in MM.

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Section: Anti-bcma Cd3 Bi- or Trispecific Moleculesmentioning

confidence: 99%

Targeting B Cell Maturation Antigen (BCMA) in Multiple Myeloma: Potential Uses of BCMA-Based Immunotherapy

2018

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“…In the phase 3 clinical trial 23 comparing velcade/dexamethasone to velcade/dexamethasone/daratumumab in 498 R/R MM patients (Castor trial) the 12-month rate of progression-free survival was 60.7% in the daratumumab group versus 26.9% in the control group. The rate of overall response was higher in the daratumumab 25 group than in the control group as well (82.9% vs. 63.2%, P<0.001), as were the rates of complete response or better (19.2% vs. 9.0%, P=0.001). After a median follow-up period of 7.4 months, the median progression-free survival was not reached in the daratumumab group and was 7.2 months in the control group (hazard ratio for progression or death with daratumumab vs. control, 0.39; 95% confidence interval, 0.28 to 0.53; P<0.001).…”

Section: Antibodies Targeting MM Cellsmentioning

confidence: 83%

“…Pre-clinical evaluation was promising in mouse and monkeys and further investigations are on going although the short half life of the molecule might require frequent infusions 41 . Several other bi-specific antibodies are under development and include TNB383B, TNB-384B, Ab-957, EM801 and BCMA-TCB2, that are also IgG-based human bi-specific antibodies with two binding sites for BCMA and CD3 with significant toxicity on MM cells in pre-clinical models 25,42,43 . PF-3135 is a humanized immunoglobulin G (IgG2a) CD3 and BCMA bispecific monoclonal antibody that is now evaluated in an ongoing phase 1 clinical trial () 44 .…”

Section: Antibodies Targeting MM Cellsmentioning

confidence: 99%

Novel Agents in Multiple Myeloma

Szalat¹,

Munshi²

2019

Cancer J

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The therapeutic landscape of multiple myeloma (MM) has dramatically changed in the last 15 years with the advent of Imids and proteasome inhibitors. However, majority of MM patients relapse and new therapies are needed. Various agents with diverse mechanisms of action and distinct targets, including cellular therapies, monoclonal antibodies, and small molecules are currently under investigation. In this review, we report novel drugs recently approved or under advanced investigation that will likely be incorporated in the near future as new standard for MM treatment, focusing on their mechanisms of action, cellular targets and stage of development.

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“…Bispecific T‐cell engagers (BiTEs) are a type of bispecific antibody that targets a tumour epitope and a T‐cell antigen, commonly CD3. Several BiTEs that target BCMA and CD3 have been developed and BCMA has been the focus of the majority of BiTEs for the treatment of MM to date 79–83 . These BiTEs are in the early stages of clinical development but in a phase 1 trial of CC‐93269, an anti‐BCMA BiTE, 12 patients with RRMM who received >6 mg achieved an overall response rate of 83% and a minimal residual disease negativity rate to 10 −5 of 75% 84 .…”

Section: Future Directionsmentioning

confidence: 99%

“…Several BiTEs that target BCMA and CD3 have been developed and BCMA has been the focus of the majority of BiTEs for the treatment of MM to date. [79][80][81][82][83] These BiTEs are in the early stages of clinical development but in a phase 1 trial of CC-93269, an anti-BCMA BiTE, 12 patients with RRMM who received >6 mg achieved an overall response rate of 83% and a minimal residual disease negativity rate to 10 À5 of 75%. 84 BiTEs that target CD38 and CD3 are also in early clinical development for RRMM as are bispecific antibodies that target BCMA and the NK-cell antigen CD16a to induce NK-mediated cell killing.…”

Section: Antibody-drug Conjugatesmentioning

confidence: 99%

Antibody‐based immunotherapy for treatment of immunoglobulin light‐chain amyloidosis

2020

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Immunoglobulin light-chain (AL) amyloidosis is a clonal plasma cell disorder characterised by production and deposition of misfolded monoclonal light chains in vital organs with potential to cause irreversible organ damage. The treatment of AL amyloidosis has evolved along the lines of multiple myeloma (MM) owing to clonal plasma cells being at the root of both disease processes. Treatment with melphalan and autologous haematopoietic cell transplantation, as well as proteasome inhibitors and immunomodulatory agents, are the standard of care for AL amyloidosis. While these treatment modalities are highly effective against the neoplastic plasma cells, patients often relapse and those with advanced disease may be unable to tolerate these treatments due to side-effects. Immunotherapy with monoclonal antibodies, bispecific antibodies, antibody-drug conjugates and chimeric antigen receptor T cells have revolutionised the treatment armamentarium for MM. These novel immunotherapy agents are in the early phases of evaluation and clinical development for patients with AL amyloidosis. The present review aims to discuss the role of novel immunotherapies currently in development and their potential for use in the treatment of AL amyloidosis.

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Development of a New BCMAxCD3 Duobody® Antibody for Multiple Myeloma

Cited by 8 publications

References 0 publications

Targeting B Cell Maturation Antigen (BCMA) in Multiple Myeloma: Potential Uses of BCMA-Based Immunotherapy

Targeting B Cell Maturation Antigen (BCMA) in Multiple Myeloma: Potential Uses of BCMA-Based Immunotherapy

Novel Agents in Multiple Myeloma

Antibody‐based immunotherapy for treatment of immunoglobulin light‐chain amyloidosis

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